Novel Bicyclic P,S-Heterocycles via Stereoselective hetero-Diels–Alder Reactions of Thiochalcones with 1-Phenyl-4H-phosphinin-4-one 1-Oxide

Thiochalcones undergo cycloaddition reactions in THF solution at 60 °C with the synthetically unexplored 1-phenyl-4H-phosphinin-4-one 1-oxide in a highly regio- and stereoselective manner, yielding hitherto unknown bicyclic P,S-heterocycles containing fused thiopyran and phosphinine rings. The stereochemical structures of two of the obtained (4+2)-cycloadducts were unambiguously assigned by means of the X-ray single-crystal analysis. Based on these assignments, a concerted mechanism of the hetero-Diels–Alder reaction via the preferred endo approach of the heterodiene from the less hindered P=O side of the phosphininone molecule is postulated to explain the established rac-(4RS,8SR,9SR,10SR)-configured (4+2)-cycloadducts isolated as major products.

Many years ago, a rare six-membered phosphorus heterocycle (4H-phosphinin-4one) was reported as a stable 1-oxide 5a [16].In recent publications, the synthesis of its dihydro derivative 5b was also described [17,18] (Figure 2).The structures of both compounds resemble the 1,4-quinone framework, strongly suggesting their potential reactivity toward dienes/heterodienes and, thus, a possible application for the synthesis of new, fused P-heterocyclic systems.This expectation is reinforced by the fact that five-membered ring congeners of phosphinine 1-oxides 5a and 5b, namely phospholene 1-oxide 6a and its derivatives 6b and 6c, as well as the dihydrophosphinine 1-oxide 7, have already been reported to act as dieno-and dipolarophiles in the cycloaddition chemistry (Scheme 2).Scheme 1.Recently described hetero-Diels-Alder reactions of thiochalcone 2 with naphthoquinone, leading to polycyclic S-heterocycle 4 [15].
Many years ago, a rare six-membered phosphorus heterocycle (4H-phosphinin-4-one) was reported as a stable 1-oxide 5a [16].In recent publications, the synthesis of its dihydro derivative 5b was also described [17,18] (Figure 2).The structures of both compounds resemble the 1,4-quinone framework, strongly suggesting their potential reactivity toward dienes/heterodienes and, thus, a possible application for the synthesis of new, fused Pheterocyclic systems.This expectation is reinforced by the fact that five-membered ring congeners of phosphinine 1-oxides 5a and 5b, namely phospholene 1-oxide 6a and its derivatives 6b and 6c, as well as the dihydrophosphinine 1-oxide 7, have already been reported to act as dieno-and dipolarophiles in the cycloaddition chemistry (Scheme 2).
Cycloaddition reactions involving the exploration of C,P-heterocycle 1-oxides as dienoor dipolarophiles are rarely described.Representative examples of such reactions, leading to a variety of polycylic P-heterocycles, as illustrated in Schemes 2-4, have already been reported.Cycloaddition reactions involving the exploration of C,P-heterocycle 1-oxides as dieno-or dipolarophiles are rarely described.Representative examples of such reactions, leading to a variety of polycylic P-heterocycles, as illustrated in Schemes 2-4, have already been reported.
The only known example of a (4+2)-cycloaddition involving the six-membered phosphinine 1-oxide 7 is depicted in Scheme 4B.However, in this instance, the observed dimerization-like cycloaddition did not occur between two molecules of 7. Instead, 7 was trapped by its double bond isomer 7′ present in the reaction mixture, leading to the stereoselective formation of the tricyclic product 12 (Scheme 4B) [25].This unexpected reaction provides an intriguing example of so-called cross-dimerizations.Scheme 4. Stereoselective dimerization of phospholene 1-oxide 6c and phosphinine 1-oxide 7 leading to polycyclic P-heterocycles 11 and 12, respectively (ref.[23,24] and [25]).The diene molecule 7' and diene framework in cycloadduct 12 are presented in red.
The objective of the present study was to investigate the reactivity of 4H-phosphinin-4-one 1-oxides 5a and 5b toward selected thiochalcone 2, which were employed as reactive heterodienes.Specifically, we aimed to elucidate the regiochemistry of the anticipated hetero-Diels-Alder reactions and the stereochemical structure of the resulting (4+2)-cycloadducts containing two heteroatoms (P and S).Additionally, the investigation of the reaction mechanism was of particular interest.
The only known example of a (4+2)-cycloaddition involving the six-membered phosphinine 1-oxide 7 is depicted in Scheme 4B.However, in this instance, the observed dimerization-like cycloaddition did not occur between two molecules of 7. Instead, 7 was trapped by its double bond isomer 7 ′ present in the reaction mixture, leading to the stereo-selective formation of the tricyclic product 12 (Scheme 4B) [25].This unexpected reaction provides an intriguing example of so-called cross-dimerizations.
The objective of the present study was to investigate the reactivity of 4H-phosphinin-4-one 1-oxides 5a and 5b toward selected thiochalcone 2, which were employed as reactive heterodienes.Specifically, we aimed to elucidate the regiochemistry of the anticipated hetero-Diels-Alder reactions and the stereochemical structure of the resulting (4+2)-cycloadducts containing two heteroatoms (P and S).Additionally, the investigation of the reaction mechanism was of particular interest.

Results and Discussion
The test experiment was carried out in THF solution at 60 • C using 1-phenyl-3-(thien-2-yl)propene-1-thione (2a) and 1-phenylphosphinin-4-one 1-oxide (5a) in a 1:1 ratio.TLC analysis revealed complete consumption of 2a after approximately 20 h.After the removal of THF in vacuum, the crude reaction mixture was analyzed by 1 H NMR, indicating the presence of two products formed in unequal amounts.The major product exhibited three signals in the non-aromatic region at 3.63-3.66,4.03-4.05,and 4.54-4.57ppm, which can be attributed to aliphatic protons.Additionally, three similar but less intense signals were observed for the minor product at 3.69-3.71,4.06-4.08,and 4.49-4.50ppm, respectively (Supplementary Figure S1).The close resemblance of the corresponding signals of the major and minor products strongly suggested that they shared the same framework with identical positions of both heteroatoms (S and P), differing most likely only in the relative stereochemistry at stereogenic centers.A comparison of the intensities of the integration lines of multiplets attributed to the major and minor components suggested a ca.7:1 ratio of these isomeric cycloadducts.
Chromatographic separation of the crude reaction mixture on a SiO 2 column afforded the major product with a melting point of 184 • C (decomposition) in a yield of 57%, using a petroleum ether/dichloromethane mixture as the eluent.The 31 P NMR spectrum showed a resonance signal at 20.9 ppm for the P atom.The HRMS spectrum of this product revealed a molecular mass [M + 1] = 435.0642,corresponding to the molecular formula C 24 H 20 O 2 PS 2 , indicative of the (4+2)-cycloadduct of 2a and 5a.Finally, single-crystal X-ray diffraction analysis confirmed the structure of the fused P,S-heterocycle 13a, with the heteroatoms located at S(1) and P(8) positions, respectively (for conventional atom numbering, see Scheme 5).In contrast to quinones (Scheme 1), no spontaneous oxidation of the initially formed cycloadducts was observed.Based on the X-ray analysis, the stereochemical structure of this diastereoisomer was determined as rac-(4RS,8SR,9SR,10SR) (Scheme 5 and Figure 3).
The aforementioned three sets of signals of the minor product could tentatively be attributed to an isomeric cycloadduct 14a with rac-(4SR,8SR,9SR,10SR) configuration (Scheme 5).However, attempts to isolate this product by column chromatography were unsuccessful.
Reactions of thiochalcones 2b-2d with 5a (molar ratio 1:1) were carried out under analogous conditions to those described for 2a.In all cases, as in the experiment with 2a, the 1 H NMR spectra obtained for the crude reaction mixtures revealed the presence of two isomeric cycloadducts of types 13 and 14, exhibiting similar sets of signals in the previously described high-field regions of the 1 H NMR spectra.However, in all cases, the yields of the postulated cycloadducts 14b-14d were consistently very low (<10%), and their attempted isolation was again unsuccessful.The major product 13b, bearing two phenyl substituents, was isolated chromatographically in 51% yield.Subsequent crystallization from petroleum ether/CH 2 Cl 2 yielded single crystals suitable for the X-ray analysis.The analysis confirmed both the regiochemical structure of 13b and the configurations of the four stereogenic centers at C(4), P(8), C(9), and C (10), indicating again the endo mode of addition in full analogy to 13a (Scheme 5 and Figure 4).lines of multiplets attributed to the major and minor components suggested a ca.7:1 ratio of these isomeric cycloadducts.
Chromatographic separation of the crude reaction mixture on a SiO2 column afforded the major product with a melting point of 184 °C (decomposition) in a yield of 57%, using a petroleum ether/dichloromethane mixture as the eluent.The 31 P NMR spectrum showed a resonance signal at 20.9 ppm for the P atom.The HRMS spectrum of this product revealed a molecular mass [M + 1] = 435.0642,corresponding to the molecular formula C24H20O2PS2, indicative of the (4+2)-cycloadduct of 2a and 5a.Finally, single-crystal X-ray diffraction analysis confirmed the structure of the fused P,S-heterocycle 13a, with the heteroatoms located at S(1) and P(8) positions, respectively (for conventional atom numbering, see Scheme 5).In contrast to quinones (Scheme 1), no spontaneous oxidation of the initially formed cycloadducts was observed.Based on the X-ray analysis, the stereochemical structure of this diastereoisomer was determined as rac-(4RS,8SR,9SR,10SR) (Scheme 5 and Figure 3).the major product with a melting point of 184 °C (decomposition) in a yield of 57%, using a petroleum ether/dichloromethane mixture as the eluent.The 31 P NMR spectrum showed a resonance signal at 20.9 ppm for the P atom.The HRMS spectrum of this product revealed a molecular mass [M + 1] = 435.0642,corresponding to the molecular formula C24H20O2PS2, indicative of the (4+2)-cycloadduct of 2a and 5a.Finally, single-crystal X-ray diffraction analysis confirmed the structure of the fused P,S-heterocycle 13a, with the heteroatoms located at S(1) and P(8) positions, respectively (for conventional atom numbering, see Scheme 5).In contrast to quinones (Scheme 1), no spontaneous oxidation of the initially formed cycloadducts was observed.Based on the X-ray analysis, the stereochemical structure of this diastereoisomer was determined as rac-(4RS,8SR,9SR,10SR) (Scheme 5 and Figure 3).The aforementioned three sets of signals of the minor product could tentatively be attributed to an isomeric cycloadduct 14a with rac-(4SR,8SR,9SR,10SR) configuration (Scheme 5).However, attempts to isolate this product by column chromatography were unsuccessful.Reactions of thiochalcones 2b-2d with 5a (molar ratio 1:1) were carried out under analogous conditions to those described for 2a.In all cases, as in the experiment with 2a, the 1 H NMR spectra obtained for the crude reaction mixtures revealed the presence of two isomeric cycloadducts of types 13 and 14, exhibiting similar sets of signals in the previously described high-field regions of the 1 H NMR spectra.However, in all cases, the yields of the postulated cycloadducts 14b-14d were consistently very low (<10%), and their attempted isolation was again unsuccessful.The major product 13b, bearing two phenyl substituents, was isolated chromatographically in 51% yield.Subsequent crystallization from petroleum ether/CH2Cl2 yielded single crystals suitable for the X-ray analysis.The analysis confirmed both the regiochemical structure of 13b and the configurations of the four stereogenic centers at C(4), P(8), C(9), and C (10), indicating again the endo mode of addition in full analogy to 13a (Scheme 5 and Figure 4).It is worth mentioning that in separate NMR experiments, the stereochemical stability of 13b was tested in CDCl3 solution at room temperature and at 60 °C, and in both cases, unchanged 13b was observed thereafter.Moreover, addition of catalytic amounts of either TFA or pyridine to the sample did not result in any detectable isomerization of It is worth mentioning that in separate NMR experiments, the stereochemical stability of 13b was tested in CDCl 3 solution at room temperature and at 60 • C, and in both cases, unchanged 13b was observed thereafter.Moreover, addition of catalytic amounts of either TFA or pyridine to the sample did not result in any detectable isomerization of 13b, neither at room temperature nor after heating at 60 • C. The observed lack of isomerization thus allowed us to exclude the possibility that the obtained minor products were formed via keto-enol equilibration of the corresponding major products under the reaction conditions.Considering the complete face selectivity recorded thus far for all known cycloadditions of cyclic organophosphorus dienophiles, which are exclusively attacked by a diene from their P=O bearing side (cf.Schemes 5 and 6), it became most plausible that the stereochemistry of the minor product 14 reflects the exo mode of their formation, as tentatively assigned (cf.Scheme 5).It is worth mentioning that in separate NMR experiments, the stereochemical stability of 13b was tested in CDCl3 solution at room temperature and at 60 °C, and in both cases, unchanged 13b was observed thereafter.Moreover, addition of catalytic amounts of either TFA or pyridine to the sample did not result in any detectable isomerization of 13b, neither at room temperature nor after heating at 60 °C.The observed lack of isomerization thus allowed us to exclude the possibility that the obtained minor products were formed via keto-enol equilibration of the corresponding major products under the reaction conditions.Considering the complete face selectivity recorded thus far for all known cycloadditions of cyclic organophosphorus dienophiles, which are exclusively attacked by a diene from their P=O bearing side (cf.Schemes 5 and 6), it became most plausible that the stereochemistry of the minor product 14 reflects the exo mode of their formation, as tentatively assigned (cf.Scheme 5).Notably, the attempted hetero-Diels-Alder reaction of 5a with the isomeric thiochalcone 2 ′ a (3-phenyl-1-(thien-2-yl)propene) in THF at 60 • C was unsuccessful, resulting in the decomposition of the starting materials.Apparently, the substitution pattern in the starting thiochalcone also influences the outcome of the studied reactions.
Structure analysis of cycloadducts 13a and 13b: In our research endeavor, we successfully acquired crystal samples of compounds 13a and 13b, which proved to be suitable for conducting X-ray single-crystal experiments.Both compounds exhibit crystal structures within the centrosymmetric P2 1 /c space group.Consequently, the crystal samples applied in the analysis contain racemic mixtures of inversion-equivalent enantiomeric forms, aligning with the anticipated outcome within the context of our synthesis procedure.For a detailed insight into the absolute configuration of all four chiral centers in molecules of 13a and 13b, refer to Scheme 5. Furthermore, our crystallographic analysis revealed the presence of two molecules within the symmetry-independent cell unit in both crystals.There is no pseudo-symmetry between the molecules in the asymmetric unit.Each molecule possesses its own structural characterization in both experimentally treated samples.
Remarkably, these molecules within the symmetry-independent unit display identical absolute configurations.
The molecular architecture of both compounds is characterized by two fused heterocyclic rings, as depicted in Figures 3 and 4. Notably, the C(9) and C(10) centers serve as common elements in both heterocycles.The hydrogen atoms attached to these carbon atoms adopt a cis configuration, leading to a distinctive nonplanar geometry of this primary molecular moiety and, consequently, influencing the overall molecular structure.This nonplanarity is reflected in the formation of dihedral angles of 79.74 • and 75.16 • for compounds 13a and 13b, respectively.In both crystal samples, the heterocyclic rings adopt a half-boat conformation, with the C(9) and C(10) atoms positioned above the mean plane of the rings.The distance between the carbon atoms at the apex position and the planar fragments of the rings is in the range of 0.654(3)-0.756(3)Å. Importantly, the heteroatoms S and P are always in the plane of their parent rings.
The planarity of other rings conforms to expectations, with their positioning relative to the bearing fragment determined by crystal packing, exhibiting no anomalous behavior.
An intriguing observation arises from the absence of classic H-bond-donating groups in both molecules, thereby precluding the presence of traditional H-bonds (e.g., O-H . . .O or N-H . . .O type) responsible for stabilizing the crystal lattice.Instead, we identified numerous weak short contacts of C-H . . .A (where A = S and O), potentially serving as stabilizing interactions.Notably, our attention is particularly drawn to a short contact of P=O . . .C sp 2 type, with O . . .C distances of 2.994(2) Å and 3.006(2) Å for compounds 13a and 13b, respectively.The corresponding P=O . . .C angles are measured to be 130.6(1) • and 137.5(1) • .Importantly, the involved carbon atoms belong to strongly polarized CO carbonyl groups, suggesting that these interactions may rival hydrogen bonding in terms of strength.As already postulated [26], such interactions exhibit a comparable strength to hydrogen bonding and are notably directional due to the partial atomic charge distribution within the interacting fragments.We are expecting that this specific P=O . . .C interaction may be a leading one among all, which stabilizes crystals of 13a and 13b.
Mechanistic consideration: The (4+2)-cycloadditions of electron-rich thiochalcone 2 with the phosphorus-containing dienophile 5a, considered as an electron-deficient dienophile, are reported for the first time.Therefore, the mechanism of these hetero-Diels-Alder reactions depicted in Scheme 6 deserves a brief comment.
In recent decades, mechanisms of cycloaddition reactions have been studied intensively.Alongside the 'classical' interpretation based on the assumption of concerted pathways, stepwise processes via zwitterionic or diradical intermediates have also been discussed [27][28][29][30].It is well known that the large energy gap between HOMO and LUMO energies of both reactants, i.e., 1,3-dipole and dipolarophile in the case of (3+2)cycloadditions [2], and diene and dienophile in the case of Diels-Alder reactions [31], favors stepwise mechanisms.
In our opinion, the studied reactions follow the classical concerted (but asynchronous) mechanism, and the preferred endo-attack of the heterodiene from the less hindered P=O side (face selectivity) of the organophosphorus compound leads to the isolated major cycloadduct rac-(4RS,8SR,9SR,10SR)-13 (Scheme 6).The reactions occur with complete regioselectivity and lead to the formation of the C-S bond exclusively at the β-C atom.Moreover, it has already been well documented that the α,β-unsaturated P-heterocyclic dienophiles undergo cycloaddition reactions with 1,3-dipoles [21,22] as well as with dienes [19,20] via the approach from the P=O bearing face, and this spatial preference is observed for both the endo and the exo mode of addition [21,22].The alternative exo attack results in the formation of (4+2)-cycloadduct 14 with an inverted configuration at the C( 4) atom (Scheme 6).

Experimental: X-ray Structure Determination of 13a and 13b
X-ray diffraction data for 13a and 13b were collected on an XtaLAB Synergy, Dualflex, HyPix diffractometer (Rigaku, Akishima, Japan).Integration of the intensities and corrections for Lorentz effects, polarization effects, and analytical absorption were performed with CrysAlis PRO [32].Using Olex2 [33], the structures were solved with the SHELXT [34] structure solution program using Intrinsic Phasing and refined with the SHELXL [35] refinement package using Least Squares minimization.The hydrogen atoms were introduced in the calculated positions with an idealized geometry and constrained using a rigid body model with isotropic displacement parameters equal to 1.2 of the equivalent displacement parameters of their parent atoms.The molecular geometries were calculated by the PLA-TON program [36].The relevant crystallographic data are provided in Table S1.Atomic coordinates, displacement parameters, and structural factors of the analyzed crystal struc-tures are deposited with the Cambridge Crystallographic Data Centre CCDC (reference numbers: 2298978 and 2298979) [37] (for further details, see Supplementary Materials).

General Information
Commercial chemicals and solvents were used as received.If not stated otherwise, products were purified by filtration through short silica gel plugs (200-400 mesh) by using freshly distilled solvents as eluents or by recrystallization.Melting points were determined in capillaries with an Aldrich Melt-Temp II (St. Louis, MO, USA), and they are uncorrected.NMR spectra were taken with a Bruker AVIII spectrometer (Billerica, MA, USA, 1 H NMR (600 MHz), 13 C NMR (151 MHz), and 31 P NMR (243 MHz)); chemical shifts (δ) are expressed in parts per million, and they relate to residual undeuterated solvent peaks (CDCl 3 : 1 H NMR δ = 7.26, 13 C NMR δ = 77.16)or to an external standard (H 3 PO 4 : 31 P NMR δ = 0.00).IR spectra are presented in cm -1 , and they were measured with an Agilent Cary 630 FTIR spectrometer (Santa Clara, CA, USA) in neat.Mass spectra (ESI) were registered with a Varian 500-MS LC Ion Trap (Palo Alto, CA, USA).Elemental analyses were obtained with a Vario EL III (Elementar Analysensysteme GmbH, Langenselbold, Germany) instrument.
General procedure for reactions of thiochalcones 2a-2d with 4H-phosphinin-4-one 1-oxide 5a: A solution containing 1.1 mmol of the corresponding thiochalcone 2 and 1 mmol of 4H-phosphinin-4-one 1-oxide 5a dissolved in 4 mL of dry THF was heated in an oil bath at 60 • C overnight (about 20 h).After this time, the TLC test showed that starting 5a was completely consumed.The solvent was evaporated, and the remaining mixture, after the 1 H NMR examination, was purified by column chromatography (petroleum ether with increasing amounts of CH 2 Cl 2 ).Analytically pure products were obtained by crystallization from petroleum ether/CH 2 Cl 2 .
Structures of the isolated cycloadducts are presented in Figures 5-8.
Structures of the isolated cycloadducts are presented in Figures 5-8.